Contractility of the myometrium, the smooth muscle layers of the uterus, is essential for the normal progression of human pregnancy and the initiation of labour. The onset of labour is associated with increasing frequency and intensity of uterine contractions, tightening the uterus and pushing the baby from the uterus into the birth canal for delivery.
A common complication of pregnancy and labour is inadequate uterine contractions. This can lead to a delay or failure in the initiation of labour or to abnormally prolonged and difficult labour (dystocia). Dystocia can result in an assisted delivery (including forceps delivery or Caesarean section) and may result in fetal health complications such as respiratory or nerve damage, or even fetal death.
In contrast, the initiation, or increase in intensity or frequency, of uterine contractions too early in pregnancy can lead to premature labour and premature or preterm birth (defined as less than 37 weeks gestational age). Preterm birth is associated with a significant increase in infant morbidity and mortality, and places an enormous burden not only on parents but on the health system. The management of premature labour is of critical importance.
Thus, during pregnancy the timing onset and maintenance of uterine contractions is critical for the normal progression of labour and there are circumstances in which it is desirable or necessary to intervene to regulate uterine contractions (either induce or stimulate uterine contractions to avoid prolonged labour, or reduce the frequency and/or intensity of uterine contractions to avoid premature labour).
Myometrial contractility is also critical after childbirth. Following the separation of the placenta from the uterine wall, blood flow is slowed in the uterus by persistent, regular myometrial contractions. With increased clotting proteins present and blood flow slowed by uterine contractions, myometrial arteries clot. Uterine contractions following birth are generally sufficient to slow the velocity of blood flowing through the uterus to initiate blood clot formation throughout myometrium. However in some women uterine contractions are inadequate. Uncontrolled bleeding following childbirth (post partum haemorrhage) can result in significant blood loss having major health implications for the new mother and even resulting in death.
Intense uterine contractions during the menstrual cycle in non-pregnant females can also be the cause of severe pain and cramping (dysmenorrhoea).
Several types or classes of drugs are presently available either to stimulate myometrial contractility (contractile drugs) or to inhibit or reduce myometrial contractility (relaxatory drugs), however use of these drugs is typically associated with side effects beyond the uterus, most notably in the cardiovascular system, and may be contraindicated in sufferers of hypertension or hypotension. Indeed several drugs that have proved to be effective in regulating uterine contractions, such as salbutamol, have fallen out of favour and have ceased to be used due to these off-target effects.
The present inventors have now developed means of targeting drugs to the myometrium such that the appropriate drug dose is available within the uterus to have the desired effect on uterine contractions while avoiding the exposure of other parts of the body to the potentially damaging side effects of the drugs. The present invention therefore not only provides a novel means for the targeted delivery of any drug(s) to the myometrium, but also provides the opportunity to continue employment of drugs that may have systemic or other off-target side effects, including drugs the use of which in relation to the myometrium has previously ceased, thereby potentially reducing the need for the development of new drugs or other therapies.